Because of its high incidence and because of its devastating socioeconomic consequences, involutional osteoporosis is one of the most important disorders affecting the aging population. The disease causes 1.3 million fractures, including 240,000 hip fractures, each year. Almost one-third of women over age 65 years will have had vertebral fractures. The lifetime risk of hip fracture is 15% in women and 5% in men. Fifty percent of survivors cannot walk independently afterwards, and 25 to 50% are committed to long-term nursing home care. Overall costs of osteoporosis are estimated as $7 to $10 billion annually in the United States. In order to treat and to prevent this disorder we need 1) to know more about basic physiologic mechanisms regulating bone cell function, 2) to elucidate the mechanisms of disordered regulation of bone cell function in osteoporosis, 3) to define more sharply clinical risk factors for fractures, and 4) to find a safe and effective means of prevention that would be widely used by the general population of aging women. To accomplish these aims is our overall goal. The Program Project contains four independent research components and an administrative and biostatistical core. Project 1, "Pathophysiology of Osteoporosis," is the clinical investigation component. It tests the hypothesis that the disease results from impaired production of several systemic and local bone cell regulatory factors or from impaired response to them. We will search for abnormalities of systemic regulatory factors and, by testing cultured human bone cells, will assess possible local abnormalities of bone cell regulation for the first time in the study of osteoporosis. Project 2, "Record Studies of Hip Fractures" is the epidemiology component. It features a series of unique population-based retrospective (non-current, historical) cohort studies designed to determine the incidence of hip and various other age-related fractures and identify risk factors for them. In specified cohorts of patients with the risk factor, the incidence of fracture will be compared with the expected incidence rates in the community population. Project 3, "Regulation of Bone Cell Function," is the basic science component. It uses cell biology and molecular biology techniques to evaluate the effect and mechanism of action of sex steroids and growth factors on cultured normal human osteoblast-like cells. Project 4, "Preventive Therapy with Calcium," is the clinical trial component. It is designed to determine if bone loss in elderly women can be prevented or reduced by calcium supplementation as is suggested by our preliminary data.